1. Technical Field
The present invention generally relates to an improved process for the preparation of intermediates for tazarotene. More specifically, the present invention relates to an improved process for the preparation of the intermediate 4,4-dimethyl-6-ethynylthiochroman using a Vilsmeier Haack reaction.
2. Description of the Related Art
The present invention is directed towards an improved process for the preparation of intermediates of tazarotene (also known as ethyl-6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]) of Formula I:
Tazarotene is a member of the acetylenic class of retinoids and is a prodrug that is converted to its active drug form, known as AGN 190299, in most biological systems by rapid deesterificaion of the cognate carboxylic acid of tazarotene. AGN 190299 binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, RARγ. AGN 190299 shows relative selectivity for the RARβ and RARγ and may modify gene expression. Tazarotene is used in the treatment of psoriasis and is commercially available under the trade name Tazorac®.
A key intermediate in the preparation of tazarotene, 4,4-dimethyl-6-ethynylthiochroman (II), is prepared as shown in Scheme I:
Thiophenol (1) and 1-bromo-3-methyl-2-butene (2) are heated at reflux with sodium hydroxide in acetone resulting in phenyl-3-methylbut-2-enylsulfide (3). The phenyl-3-methylbut-2-enyl sulfide (3) is cyclized by refluxing with phosphorus pentoxide and phosphoric acid in benzene to yield 4,4-dimethylthiochroman (4). The 4,4-dimethylthiochroman (4) is reacted with acetyl chloride catalyzed by tin (IV) chloride (SnCl4) in benzene resulting in 4,4-dimethyl-6-acetylthiochroman (5). The 4,4-dimethyl-6-acetylthiochroman (5) is dehydrated with lithium diisopropylamide (LDA) and diethyl chlorophosphate in tetrahydrofuran (THF) results in the initial 6-ethenyl phosphonate intermediate (6). This intermediate undergoes further reaction with two equivalents of LDA to give 4,4-dimethyl-6-ethynylthiochroman (II).
The main disadvantages of this process include the use of difficult reagents, such as LDA, which is moisture sensitive, expensive, pyrophoric, and difficult to handle on a commercial scale, and diethyl chlorophosphate, which is highly toxic and corrosive. The process is also time consuming and includes low temperatures in an inert atmosphere, which is difficult to achieve on a commercial scale.
Accordingly, there remains a need for an improved process for preparing 4,4-dimethyl-6-ethynylthiochroman that eliminates and reduces the drawbacks of the prior art in a convenient and cost efficient manner on a commercial scale.